Process for the enzymatic preparation of enantiopure 1, 3-dioxolan-4-one and 1,3-oxathiolan-5-one derivatives

ABSTRACT

A process is provided for preparing an enantiopure 1,3-dioxolan-4-one or 1,3-oxathiolan-5-one derivative, which includes bringing a mixture containing enantiomeric 1,3-dioxolan-4-one or 1,3-oxathiolan-5-one derivatives and an enzyme with hydrolytic activity into contact in the presence of a nucleophile. Cleaving a dioxolanone/oxathiolanone ring of one enantiomer occurs by the enzyme with hydrolytic activity and, after the cleavage of one enantiomer has taken place, the uncleaved enantiomer of the 1,3-dioxolan-4-one or 1,3-oxathiolan-5-one derivative is isolated.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The invention relates to a process for the enzymatic preparationof enantiopure 1,3-dioxolan-4-one and 1,3-oxathiolan-5-one derivatives.

[0003] 2. The Prior Art

[0004] Enantiopure derivatives are used as starting materials andintermediates in the synthesis of agrochemicals and pharmaceuticals.Many of these compounds are currently prepared and marketed as racemateor mixture of diastereomers. However, in many cases, the desiredphysiological effect is brought about by only oneenantiomer/diastereomer. The other isomer is, in the most favorablecase, inactive, but it may also counteract the desired effect or even betoxic. Processes for separating racemates are therefore of increasingimportance for the preparation of compounds of high enantiopurity.

[0005] It is known that racemates of chiral compounds can be separatedwith the aid of enzymes. A large number of publications describeenzymatic kinetic resolutions of racemates of esters with lipases andesterases. However, to date, there is no process which permits thesimple separation of 1,3-dioxolan-4-one and 1,3-oxathiolan-5-onederivatives. Enantiopure 1,3-dioxolan-4-ones are of great interest forthe preparation of compounds with antiviral activity, such as, forexample, the 1,3-dioxolanyl-nucleoside “dioxolane-T” (NB =thymine inequation 1) and similar structures (Bioorg. Med. Chem. Lett. 1993, 3(2),pp. 169-174).

[0006] Equation 1

[0007] For preparing enantiopure 1,3-dioxolanyl-nucleosides, theseparation into the enantiomers has to date been carried out at theconsiderably more costly nucleoside stage. This process was describedfor the first time by L. J. Wilson et al. (Bioorg. Med. Chem. Lett.1993, 3(2), pp. 169-174). The butyric ester of the primary hydroxylgroup of a 1,3-dioxolanyl-nucleoside is in this case hydrolyzed with theaid of pig liver esterase, and the two pure enantiomers are thusobtained in good optical yields. WO 00/22157 (inventors: Yao, Y. et al.)describes a variant of this process by resolution in nonhomogeneoussystems.

[0008] Enantiopure 1,3-oxathiolan-5-ones are likewise of great interestfor the preparation of compounds with antiviral activity, such as, forexample, the 1,3-oxathiolanyl-nucleoside Coviracil® (also Emtricitabine,formerly FTC,4-amino-5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone;equation 2) and similar structures (J. Org. Chem. 1992, 57(21), pp.5563-5565, WO 91/11186, WO 92/14743, WO 00/22157).

[0009] Equation 2

[0010] For preparing enantiopure 1,3-oxathiolanyl-nucleosides it ispossible for the separation into the enantiomers to take place atvarious stages. Thus, an enzymatic racemate resolution is possible atthe oxathiolanone stage. This is described by Liotta et al. (WO91/11186). In this case, the stereoselection is achieved by enzymaticcleavage of an ester substituent in position 2 of the oxathiolane ring(equation 3).

[0011] Equation 3

[0012] An example which is mentioned is the hydrolysis of the butyricester (R═C₃H₇) in the presence of pig liver esterase (PLE).

[0013] The second possibility is racemate resolution at the considerablymore costly nucleoside stage. This process is described by Liotta et al.(J. Org. Chem. 1992, 57(21), pp. 5563-5565 and WO 92/14743). In thiscase, various ester acyl groups of the nucleoside racemate arestereoselectively eliminated in the presence of lipases or proteases(equation 4).

[0014] Equation 4

[0015] In some cases, high enantiomeric excesses (ee(ester) >98%) areachieved with good yields (y(ester) 45%).

[0016] An improvement of the process of WO 92/14743 is to be found in WO00/22157 (inventors: Yao, Y. et al.) through the use of non-homogeneousreaction systems (addition of water-immiscible cosolvents) forresolution of racemates of oxathiolanyl-nucleosides.

[0017] These processes of racemate resolution at a very late stageentail the serious disadvantage of unnecessary use of materials and longplant usage, because the maximum yield of a racemate resolution is 50%.The remaining 50% (the compound with the wrong handedness) is usuallydiscarded.

SUMMARY OF THE INVENTION

[0018] It is an object of the present invention to provide a process forpreparing enantiopure 1,3-dioxolan-4-one and 1,3-oxathiolan-5-onederivatives which is cost-effective and avoids the disadvantagesmentioned.

[0019] The object is achieved by a process in which a mixture containingenantiomeric 1,3-dioxolan-4-one or 1,3-oxathiolan-5-one derivatives andan enzyme with hydrolytic activity are brought into contact in thepresence of a nucleophile, whereupon the dioxolanone or oxathiolanonering of one enantiomer is cleaved by the enzyme with hydrolytic activityand, after the cleavage of one enantiomer has taken place, the uncleavedenantiomer of the 1,3-dioxolan-4-one or 1,3-oxathiolan-5-one derivativeis isolated.

[0020] The process of the invention separates a mixture of enantiomersat the dioxolanone or oxathiolanone stage and thus provides anenantiopure derivative which then makes it possible for an enantiopure1,3-dioxolanyl- or 1,3-oxathiolanyl-nucleoside to be prepared in amanner known per se. 1,3-Dioxolan-4-ones and 1,3-oxathiolan-5-ones havein the ring a hydrolysis-labile ester linkage which can be cleaved by anenzyme-catalyzed reaction. It has been found, surprisingly, that thisester linkage in the dioxolanone or oxathiolanone ring can be cleaved byan enzyme with hydrolytic activity both with high enantioselectivity andwith high regioselectivity in relation to other hydrolysis-labile groupspresent in the compound.

[0021] The process of the invention therefore preferably comprisesbringing a mixture containing enantiomeric 1,3-dioxolan-4-one or1,3-oxathiolan-5-one derivatives into contact with an enzyme which isable to cleave an ester linkage in the presence of a nucleophile of thegeneral formula NuH so that one enantiomer is preferentially cleaved.

[0022] This cleavage is depicted diagrammatically in equation 5.

[0023] Equation 5

[0024] where X=oxygen or sulfur and the radicals R¹ and R² are differentand are selected independently of one another from the group consistingof H, substituted or unsubstituted C₆-C₁₈-aryl, C₃-C₁₈-heteroaryl,C₁-C₁₈-alkyl, C₂-C₁₈-alkenyl, C

-C₁₈-alkynyl, C₂-C₁₈-aryl-C₁-C₁₈-alkyl, C₃-C₁₈-heteroaryl-C₁-C₁₈-alkyl,C

-C

-aryl-C₂-C₁₈-alkenyl, C

-C₁₈-heteroaryl-C

-C

-alkenyl, C

-C₁₈-alkoxy-C₁-C₁₈-alkyl, C₁-C₁₈-alkoxy-C₂-C₁₈-alkenyl, C

-C₁₈-aryloxy-C₁-C₁₈-alkyl, C₆-C₁₈-aryloxy-C₂-C₁₈-alkenyl, C

-C

-cycloalkyl, C

-C

-cycloalkyl-C₁-C₁₈-alkyl, C

-C

-cycloalkyl-C

-C₁₈-alkenyl, and CR⁸R⁹—O

—(CO)_(m)—R¹⁰ and the radicals R³ and R⁴ are selected independently ofone another from the group consisting of substituted or unsubstitutedC₁-C₁₈-aryl, C₁-C₁₈-heteroaryl, C₁-C₁₈-alkyl, C₂-C₁₈-alkenyl,C₂-C₁₈-alkynyl, C

-C₁₈-aryl-C₁-C₁₈-alkyl, C₃-C₁₈-heteroaryl-C₁-C₁₈-alkyl,C₆-C₁₈-aryl-C₂-C₁₈-alkenyl, C

-C₁₈-heteroaryl-C₂-C₁₈-alkenyl, C₁-C₁₈-alkoxy-C₁-C₁₈-alkyl,C₁-C₁₈-alkoxy-C

-C₁₈-alkenyl, C₆-C₁₈-aryloxy-C₁-C₁₈-alkyl,C₆-C₁₈-aryloxy-C₂-C₁₈-alkenyl, C

-C

-cycloalkyl, C

-C

-cycloalkyl-C₁C₁₈-alkyl, and C

-C₂-cycloalkyl-C₂-C₁₈-alkenyl or the radicals R³ and R⁴ form, togetherwith the carbon to which they are bonded, an unsubstituted orsubstituted or a heteroatom-containing cycloalkylidene and Nu is OR⁵,SR⁵ or NR⁶R⁷, where

[0025] the radicals R⁵ are selected from the group consisting of H,substituted or unsubstituted C₁-C₁₈-alkyl, C₂-C₁₈-alkenyl,C₂-C₁₈-alkynyl, C₆-C₁₈-aryl-C₁-C₁₈-alkyl,C₃-C₁₈-heteroaryl-C₁-C₁₈-alkyl, C₆-C₁₈-aryl-C₂-C₁₈-alkenyl, andC₃-C₁₈-heteroaryl-C₂-C₁₈-alkenyl, and the radicals R⁶ and R⁷ areselected independently of one another from the group consisting of H,substituted or unsubstituted C₁-C₁₈-alkyl, C₂-C₁₈-alkenyl,C₂-C₁₈-alkynyl, C₄-C₁₈-aryl, C₃-C₁₈-heteroaryl,C₆-C₁₈-aryl-C₁-C₁₈-alkyl, C₃-C₁₈-heteroaryl-C₁-C₁₈-alkyl,C₆-C₁₈-aryl-C₂-C₁₈-alkenyl, and C

-C₁₈-heteroaryl-C₂-C₁₈-alkenyl and the radicals R

and R

are selected independently of one another from the group consisting ofsubstituted or unsubstituted C₆-C₁₈-aryl, C

-C

-heteroaryl, C₁-C₁₈-alkyl, C

-C₁₈-alkenyl, C₂-C₁₈-alkynyl, C₆-C₁₈-aryl-C₁-C₁₈-alkyl, C

-C₁₈-heteroaryl-C₁C₁₈-alkyl, C

-C₁₈-aryl-C₂-C₁₈-alkenyl, C

-C₁₈-heteroaryl-C

-C

-alkenyl, C₁-C₁₈-alkoxy-C₁-C₁₈-alkyl, C₁-C₁₈-alkoxy-C₂-C₁₈-alkenyl, C

-C

-aryloxy-C₁-C₁₈-alkyl, C₆-C₁₈-aryloxy-C₂-C₁₈-alkenyl, C

-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₁₈-alkyl, and C

-C

-cycloalkyl-C₂-C₁₈-alkenyl or the radicals R⁸ and R

form, together with the carbon to which they are bonded, anunsubstituted or substituted or a heteroatom-containing cycloalkylidene,and m and n are, independently of one another, 0 or 1, and the followingapplies to the radical R¹⁰: if m is 0 then the radical R¹⁰ is selectedfrom the group consisting of substituted or unsubstituted C₁-C₁₈-alkyl,C₂-C₁₈-alkenyl or C₂-C₁₈-alkynyl, substituted or unsubstitutedC₆-C₁₈-aryl, C₃-C₁₈,-heteroaryl, and substituted or unsubstitutedsilaalkyl or silaaryl, and if m is 1 then the radical R¹⁰ is selectedfrom the group consisting of substituted or unsubstituted aryl,substituted or unsubstituted C₁-C₁₈-alkyl, C₂-C₁₈-alkenyl orC₂-C₁₈-alkynyl.

[0026] Where the radicals are substituted radicals, these are preferablysubstituted by alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl,alkoxy, carboxylate, alkoxycarbonyl, amino, nitro or halo radicals.

[0027] Where the abovementioned radicals contain a heteroatom, it ispreferably O, N or S.

[0028] Mixtures of enantiomers of the general formula (I)

[0029] where R³, R⁴, R⁸ and R⁹ have the meaning mentioned above, and R¹¹are substituted or unsubstituted, branched or unbranched C₁-C₁₈-alkyl,C₂-C₁₈-alkenyl or C₂-C₁₈-alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted silaalkyl or silaaryl, or R¹¹ is COR¹⁰where R¹⁰ has the meaning mentioned above, are preferably used.

[0030] Mixtures of enantiomers of the general formula (II)

[0031] where R³ and R² have the meaning mentioned above, and R¹⁰ isselected from the group consisting of substituted or unsubstituted aryl,substituted or unsubstituted C₁-C₁₈-alkyl, C₂-C₁₈-alkenyl and C

-C

-alkynyl, are particularly preferably used.

[0032] The nucleophile NuH is preferably an oxygen-containingnucleophile OR⁵.

[0033] The oxygen-containing nucleophile is particularly preferably alower, unbranched alcohol, (e.g. methanol (R⁵═CH₃) or ethanol (R^(5═CH)₂CH₃)) or water (R

═H).

[0034] All enzymes able to cleave an ester linkage are in principlesuitable for the process of the invention. Preference is given to alipase or esterase of class 3.1 of the international enzymenomenclature, Committee of the International Union of Biochemistry andMolecular Biology. Because they are easy to obtain, particularpreference is given to lipases or esterases of microbial origin, pigpancreatic lipase, horse liver esterase or pig liver esterase.

[0035] Examples of enzymes of microbial origin which may be mentionedare enzymes from fungi, yeasts or bacteria such as, for example,Alcaligenes sp., Aspergillus niger, Aspergillus oryzae, Bacillus sp.,Bacillus stearothermophilus, Bacillus thermoglucosidasius, Candidaantarctica, Candida lipolytica, Candida rugosa, Chromobacteriumviscosum, Geotrichium candium, Mucor miehei, Penicillium camembertii,Penicillium roquefortii, Pseudomonas cepacia, Pseudomonas fluorescens,Pseudomonas sp., Rhizomucor javanicus, Rhizopus arrhizus, Rhizopusniveus, Saccharomyces cerevisae, Thermoanaerobium brockii, Thermomyceslanuginosa. Particular preference is moreover given to lipases andesterases from Candida species such as, for example, Candida antarcticaB.

[0036] Very particular preference is given to Novozym® 435, 525(commercially available from Novo, Denmark), Chirazym® L2, E1, E2 and L7(commercially available from Boehringer Mannheim, Germany) as enzyme.

[0037] The enzyme is employed in the reaction directly or in immobilizedform bound to a wide variety of carriers.

[0038] An immobilized form can be prepared in a manner known per se.This is possible, for example, by the enzyme being dissolved in a bufferat a suitable pH and then being passively adsorbed onto the carrier suchas, for example, diatomaceous earth (Celite®), activated carbon,alumina, silica gel, kieselguhr, monodisperse soluble organosiloxaneparticles or resins (e.g. Amberlite®, Dowex®). An alternativepossibility is for the enzymes also to be covalently bonded to thecarrier (e.g. polystyrene or epoxy resins such as Eupergit®). An enzymewhich has been bound to a carrier in this way, for example, can be driedby lyophilization.

[0039] The amount of enzyme to be employed in the process of theinvention depends on the nature of the precursor and of the product andon the activity of the enzyme preparation. The amount of enzyme which isoptimal for the reaction can be established by simple preliminary tests.

[0040] Depending on the enzyme, the enzyme/substrate ratio, calculatedas molar ratio between enzyme and dioxolanone/oxathiolanone derivative,is usually between 1:1 000 and 1:50 000 000 or more, preferably from1:10 000 to 1:5 000 000.

[0041] The process of the invention can be carried out both in purenucleophile (NuH) as solvent and in mixtures of the nucleophile (NuH)with aprotic or protogenic solvents or mixtures of solvents as long asthese do not affect the reactivity of the enzyme with hydrolyticactivity or lead to unwanted side reactions.

[0042] The reaction is advantageously carried out in a mixture of thenucleophile and a suitable solvent. Examples of suitable solvents arealiphatic or aromatic hydrocarbons such as hexane, cyclohexane,petroleum ether or toluene, halogenated hydrocarbons such as methylenechloride or chloroform, ethers such as methyl tert-butyl ether (MTBE),diethyl ether, diisopropyl ether, THF or dioxane, esters, acetonitrileor, where appropriate, alcohols which do not represent a nucleophile inrelation to the abovementioned enzymatic reaction, such as, for example,tertiary alcohols, or mixtures of said compounds.

[0043] The nucleophile/solvent ratio (v/v) is in this case preferably ina range from 1:10 000 to 1 000:1.

[0044] Mixtures of the nucleophile with aprotic solvents such as MTBE ordiisopropyl ether in a nucleophile/solvent ratio (v/v) of from 1:100 to100:1 are particularly preferred.

[0045] If water is used as nucleophile (Nu═OH), it is possible formaintenance of a preset pH to adjust the latter by adding a buffer. AnNa ₂HPO₄/NaHPO, buffer with a pH of 7.0 is preferably used for thispurpose. It is also possible for the same purpose to meter in an aqueousalkali, preferably a solution of an alkali metal hydroxide in water,particularly preferably an aqueous solution of NAOH or KOH.

[0046] The reaction is advantageously carried out at a temperaturebetween 0° C. and 75° C., preferably between 10° C. and 60° C.,particularly preferably between 20° C. and 50° C.

[0047] The reaction times depend on the substitution pattern of thedioxolanone, choice of the nucleophile and solvent and the nature andamount of the enzyme and are between 10 minutes and 7 days. The reactiontimes are preferably between 1 and 48 hours.

[0048] The progress of the reaction can easily be followed byconventional methods, for example by HPLC. The progress of the reactioncan preferably be determined by measuring the change in the opticalrotation of the reaction solution in a polarimeter. The progress of thereaction is particularly preferably determined on line by measuring theoptical rotation in a subsidiary circuit of the reactor. The terminationof the reaction can depend on the desired result (high conversion, highenantiomeric excess of the substrate). In the ideal case, the reactionis terminated when the conversion is 50% with a high enantiopurity inthe substrate.

[0049] The reaction is preferably terminated for example by separatingthe substrate or the product from the enzyme, for example by extractionof the aqueous phase or filtration. The reaction can also be stopped byinactivating the enzyme, for example by thermal or chemicaldenaturation.

[0050] If the reaction is carried out by repeated, continuous pumping ofthe reaction solution through a container packed with enzyme (aparticularly preferred procedure), the reaction is preferably terminatedby terminating the pumping.

[0051] The uncleaved, pure enantiomer is preferably isolated by removingthe byproducts of the reaction and the solvent.

[0052] The free carbonyl compound R¹COR² resulting from the cleavage ofa 1,3-dioxolan-4-one or 1,3-oxathiolan-5-one ring and the acidderivative HXCR³R⁴CONu can be removed from the reaction solution bysimple physical operations. This preferably takes place by distillation.

[0053] It is additionally possible for further breakdown products formedon cleavage of other functional groups in the molecule to be removedeasily. This preferably takes place by distillation.

[0054] It is preferred for the low-boiling compounds to be removed firstby distillation. It has been found, surprisingly, that the alcohol (R

═H, R

═CH

OH) which is a byproduct of the racemate resolution of an esterdioxolanone (X═0; R¹═H, R^(2═CH) ₂—O—(CO)—R¹⁰)) can be removed by simpleextraction, preferably with water.

[0055] The carbonyl compound resulting from the enzymatic reaction is animportant, costly precursor for the synthesis of racemic1,3-dioxolan-4-one and 1,3-oxathiolan-5-one compounds. It is preferablyemployed, in order to save chemicals and costs, in the synthesis of1,3-dioxolan-4-ones and 1,3-oxathiolan-5-ones (see scheme 1).

[0056] Scheme 1: Recycling of the carbonyl compound resulting from theracemate resolution for the example of 1,3-dioxolan-4-ones

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0057] Other objects and features of the present invention will becomeapparent from the following detailed description considered inconnection with the accompanying examples. It is to be understood,however, that the examples are designed as an illustration only and notas a definition of the limits of the invention.

[0058] Example 1: (4-oxo-1,3-dioxolan-2-yl)methyl(+)-(R)-2-methylpropanoate (batch process)

[0059] 50.0 g (0.27 mol) of racemic (4-oxo-1,3-dioxolan-2yl) methyl2-methylpropanoate (X═0; R¹ ═H; R²═CH

—O—(CO)—CH (CH₃)₂; R³, R⁴═H) are dissolved in a mixture of 185 ml ofMTBE and 185 ml of methanol (Nu=OCH,) in a 1 1 4-necked flask. 2.6 g ofNovozym® 435 are added to this solution, and the mixture is stirredvigorously.

[0060] A polarimeter is connected via a bypass system to the 4-neckedflask and is used to follow the progress of the reaction throughmeasurement of the optical rotation of the solution. When the desiredenantiopurity (reaction followed by chiral GC) is reached, the reactionis terminated by filtering the reaction mixture to remove undissolvedenzymes. The reaction mixture is then concentrated in vacuo. The residueis then taken up in 100 ml of MTBE and washed twice with 100 ml of watereach time. The organic phase is dried over Na₂SO₄ and then freed ofsolvent in vacuo. The crude product is purified by distillation.

[0061] Yield: 10.3 g (0.05 mol; 20%)

[0062] Boiling point: 55° C. (0.02 mbar)

[0063] [α]_(D) ²⁰=+19.8 (neat); ee>98%

[0064] Example 2: (4-Oxo-1,3-dioxolan-2-yl)methyl(+)-(R)-2-methylpropanoate (column process)

[0065] 50.0 g (0.27 mol) of racemic (4-oxo-1,3-dioxolan-2-yl) methyl2-methylpropanoate (X═0; R¹═H; R²═CH

—O—(CO)—CH (CH

); R³, R⁴═H) are dissolved in a mixture of 185 ml of MTBE and 185 ml ofmethanol (Nu═OCH₃) in a thermostatted 0.6 1 glass flask. A separateglass column is packed with 1.3 g of Novozym® 435, and thesubstrate/solvent mixture is pumped via a tubing system through theglass column (flow rate 600 ml/h).

[0066] The reaction is stopped (after 25 h) by terminating the pumping,and the crude product is purified as described in example 1.

[0067] Examples 3-8:

[0068] The following examples were carried out in accordance with themethod of example 1. Selectivity according to Substituents in equation 5Racemate Product Sih* 3 X = O; R¹ = H; R² = —CH₂—C₆H₅R³, R⁴ = H

(+)-2-Methylphenyl- 1,3-dioxolan-4-one 11 4 X = O; R¹ = H; R² =—C₆H₁₁R³, R⁴ = H

(+)-2-Cyclohexyl-1,3- dioxolan-4-one 65 5 X = O; R¹ = H; R² =—CH(CH₃)₂R³, R⁴ = H

(+)-2-iso-Propyl-1,3- dioxolan-4-one 14 6 X = O; R¹ = H; R² = —C₇H₁₅R³,R⁴ = H

(+)-2-Heptyl-1,3- dioxolan-4-one 13 7 X = S; R¹ = H; R² = —C₆H₁₁R³, R⁴ =H

(+)-2-Cyclohexyl-1,3- oxathiolan-5-one 65

[0069] 8 X = S; R¹ = H; R² = —CH₂O(CO)—CH(CH₃)₂R³, R⁴ = H

(+)-Isobutyryloxy- methyl-1,3-oxathiolan- 5-one 65

[0070] Accordingly, while only several embodiments of the presentinvention have been shown and described, it is obvious that many changesand modifications may be made thereunto without departing from thespirit and scope of the invention.

What is claimed is:
 1. A process for preparing an enantiopure1,3-dioxolan-4-one derivative or an enantiopure 1,3-oxathiolan-5-onederivative, which comprises bringing a mixture containing a substanceselected from the group consisting of an enantiomeric 1,3-dioxolan-4-onederivative and an enantiomeric 1,3-oxathiolan-5-one derivative and anenzyme with hydrolytic activity into contact in the presence of anucleophile; cleaving a ring of one enantiomer selected from the groupconsisting of the 1,3-dioxolan-4-one ring and the 1, 3-oxathiolan-5-onering by the enzyme with hydrolytic activity; and, after the cleaving ofone enantiomer has taken place, isolating an uncleaved enantiomerselected from the group consisting of the 1,3-dioxolan-4-one derivativeand 1,3-oxathiolan-5-one derivative.
 2. The process as claimed in claim1, wherein the mixture containing a substance selected from the groupconsisting of the enantiomeric 1,3-dioxolan-4-one derivative and theenantiomeric 1,3-oxathiolan-5-one derivative is cleaved by means of anenzyme which is able to cleave an ester linkage in the presence of anucleophile (NuH) as depicted in the equation,

Equation 5 where X=oxygen or sulfur and the radicals R

and R

are different and are selected independently of one another from thegroup consisting of H, substituted or unsubstituted C₆-C₁₈-aryl,C₃-C₁₈-heteroaryl, C₁-C₁₈-alkyl, C

-C₁₈-alkenyl, C

-C₁₈-alkynyl, C₆-C₁₈-aryl-C₁-C₁₈-alkyl, C₃-C₁₈-heteroaryl-C₁-C₁₈-alkyl,C

-C

-aryl-C

-C₁₈-alkenyl, C₃-C₁₈-heteroaryl-C

-C₁₈-alkenyl, C

-C₁₈-alkoxy-C₁-C₁₈-alkyl, C₁-C₁₈-alkoxy-C

-C₁₈-alkenyl, C

-C₁₈-aryloxy-C₁-C₁₈-alkyl, C₆-C₁₈-aryloxy-C₂-C₁₈-alkenyl,C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₁₈-alkyl, C₃-C₈-cycloalkyl-C₂-C

-alkenyl, and CR⁸R⁹—O_(n)—(CO)_(m)—R¹⁰ and the radicals R³ and R⁴ areselected independently of one another from the group consisting ofsubstituted or unsubstituted C₆-C₁₈-aryl, C₃-C₁₈-heteroaryl,C₁-C₁₈-alkyl, C₂-C₁₈-alkenyl, C₂-C₁₈-alkynyl, C₆-C₁₈-aryl-C₁-C₁₈-alkyl,C₃-C₁₈-heteroaryl-C₁-C₁₈-alkyl, C-C₁₈-aryl-C₂-C₁₈-alkenyl,C₃-C₁₈-heteroaryl-C₂-C₁₈-alkenyl, C₁-C₁₈-alkoxy-C₁-C₁₈-alkyl,C₁-C₁₈-alkoxy-C₂-C₁₈-alkenyl, C₆-C₁₈-aryloxy-C₁-C₁₈-alkyl,C₆-C₁₈-aryloxy-C₂-C₁₈-alkenyl, C₃-C₈-cycloalkyl,C₃-C₈-cycloalkyl-C₁-C₁₈-alkyl, and C₃-C₈-cycloalkyl-C₂-C₁₈-alkenyl orthe radicals R

and R⁴ form, together with the carbon to which they are bonded, anunsubstituted or substituted or a heteroatom-containing cycloalkylideneand Nu is OR

, SR

or NR

R⁷, where the radical R

is selected from the group consisting of H, substituted or unsubstitutedC₁-C₁₈-alkyl, C₂-C₁₈-alkenyl, C

-C₁₈-alkynyl, C

-C₁₈-aryl-C

-C₁₈-alkyl, C₃-C₁₈-heteroaryl-C₁-C₁₈-alkyl, C

-C₁₈-aryl-C

₂-C₁₈-alkenyl, C₃-C₁₈-heteroaryl-C₂-C₁₈-alkenyl, and the radicals R

and R

are selected independently of one another from the group consisting ofH, substituted or unsubstituted C₁-C₁₈-alkyl, C

-C₁₈-alkenyl, C₂-C₁₈-alkynyl, C₆-C₁₈-aryl, C₃-C₁₈-heteroaryl, C

-C₁₈-aryl-C₁-C₁₈-alkyl, C₃-C₁₈-heteroaryl-C₁-C₁₈-alkyl, C

-C₁₈-aryl-C₂-C₁₈-alkenyl, and C₃-C₁₈-heteroaryl-C₂-C₁₈-alkenyl and theradicals R⁸ and R⁹ are selected independently of one another from thegroup consisting of substituted or unsubstituted C₆-C₁₈-aryl,C₃-C₁₈-heteroaryl, C₁-C₁₈-alkyl, C₂-C₁₈-alkenyl, C₂-C₁₈-alkynyl,C₆-C₁₈-aryl-C₁-C₁₈-alkyl, C₃-C₁₈-heteroaryl-C₁-C₁₈-alkyl,C₆-C₁₈-aryl-C₂-C₁₈-alkenyl, C₃-C₁₈-heteroaryl-C

-C₁₈-alkenyl, C₁-C₁₈-alkoxy-C₁-C₁₈-alkyl, C₁-C₁₈-alkoxy-C₂-C₁₈-alkenyl,C

-C₁₈-aryloxy-C₁-C₁₈-alkyl, C₆-C₁₈-aryloxy-C₂-C₁₈-alkenyl, C

-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C

-C₁₈-alkyl, and C₃-C₈-cycloalkyl-C₂-C₁₈-alkenyl or the radicals R⁸ and R

form, together with the carbon to which they are bonded, anunsubstituted or substituted or a heteroatom-containing cycloalkylidene,and m and n are, independently of one another, 0 or 1, and the followingapplies to the radical R¹⁰: if m is 0 then the radical R¹⁰ is selectedfrom the group consisting of substituted or unsubstituted C₁-C₁₈-alkyl,C₂-C₁₈-alkenyl or C₂-C₁₈-alkynyl, substituted or unsubstituted₆-C₁₈-aryl, C₃-C₁₈-heteroaryl, substituted or unsubstituted silaalkyl orsilaaryl, and if m is 1 then the radical R¹⁰ is selected from the groupconsisting of substituted or unsubstituted aryl, substituted orunsubstituted C₁-C₁₈-alkyl, C₂-C₁₈-alkenyl or C₂-C₁₈-alkynyl.
 3. Theprocess as claimed in claim 1, wherein the enzyme with hydrolyticactivity is selected from the group consisting of a lipase and anesterase.
 4. The process as claimed in claim 1, wherein the enzyme isemployed in a manner selected from the group consisting of directly andin immobilized form.
 5. The process as claimed in claim 1, wherein theenzyme to dioxolanone/oxathiolanone derivative ratio, calculated asmolar ratio between enzyme and dioxolanone/oxathiolanone derivative, isfrom 1:1 000 to 1:50 000
 000. 6. The process as claimed in claim 1,wherein the nucleophile is an oxygen-containing nucleophile.
 7. Theprocess as claimed in claim 6, wherein the oxygen-containing nucleophileis selected from the group consisting of a lower unbranched alcohol andwater.
 8. The process as claimed in claim 7, wherein the lowerunbranched alcohol is selected from the group consisting of methanol andethanol.
 9. The process as claimed in claim 1, which is carried out inthe presence of a cosolvent.
 10. The process as claimed in claim 9,wherein the cosolvent is selected from the group consisting of aliphatichydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers,alcohols, esters, acetonitrile and mixtures thereof.
 11. The process asclaimed in claim 1, wherein the reaction is carried out at temperaturesbetween 0 and 75° C.
 12. The process as claimed in claim 1, wherein thereaction is carried out for between 10 minutes and 7 days.
 13. Theprocess as claimed in claim 1, wherein the uncleaved enantiomer isisolated by removing the byproducts of the reaction and the solvent. 14.The process as claimed in claim 13, wherein the byproducts are removedby a manner selected from the group consisting of extraction anddistillation.